This invention relates to compounds useful in the treatment of neuropathic pain. More particularly, this invention relates to aroyl aminoacyl pyrroles that are useful in the treatment of neuropathic pain.
The conditions grouped under the term neuropathic pain constitute an area of continuing medical need.
Neuropathic pain is defined as pain caused by aberrant somatosensory processing in the peripheral or central nervous system. Chronic or debilitating conditions, such as post-herpetic neuralgia and phantom limb syndrome, are categorized as neuropathic pain. Such conditions are widespread and cause unnecessary pain and suffering. Moreover, current methods of treating neuropathic pain are often inadequate and result in huge medical costs.
Anticonvulsants have been widely suggested for the treatment of neuropathic pain, Nadin Attal, et al., Effects of Gabapentin on the Different Components of Peripheral and Central Neuropathic Pain Syndromes: A Pilot Study, Fr. Eur. Neurol. 1998, 40(4), 191-200. Such compounds are believed to act preferentially on lancinating, shooting pain. Gabapentin induced a moderate and statistically significant relief of ongoing spontaneous pain, was particularly effective in reducing paroxysmal pain and was significantly effective on brush-induced and cold allodynia (a painful response to normally innocuous stimuli). In contrast, no effect on detection and pain thresholds to static mechanical and hot stimuli was observed. The study suggests that gabapentin is preferentially antihyperalgesic (mediates exaggerated responses to normally painful stimuli) and/or antiallodynic and similarly effective in pain due to peripheral nerve injuries or central lesions. 
Other anticonvulsants have been useful in treating neuropathic pain, Richard P. Shank, et al., Anticonvulsant Derivatives Useful in Treating Neuropathic Pain, U.S. Pat. No. 5,760,007. As disclosed in this reference, studies conducted to evaluate the efficacy of the anticonvulsant topiramate in an animal model of neuropathic pain gave evidence of pharmacological activity in treating neuropathic pain. 
Also, therapeutic compositions of anticonvulsants and non-toxic NMDA (N-methyl-D-aspartate) antagonists in neuropathic pain-alleviating amounts have been shown to block a major intracellular consequence of NMDA receptor activation, Frank S. Caruso, et al., Pharmaceutical Compositions Containing Anticonvulsants and NMDA Receptor Antagonists for Treating Neuropathic Pain, WIPO Patent No. 98/07447. This reference teaches the use of these anticonvulsants as suitable for use in this combination: lamotrigine, gabapentin, valproic acid, topiramate, famotidine, phenobarbital, diphenylhydantoin, phenytoin, mephenytoin, ethotoin, mephobarbital, primidone, carbamazepine, ethosuximide, methsuximide, phensuximide, trimethadione, benzodiazepine, phenacemide, acetazolamide, progabide, clonazepam, divalproex sodium, magnesium sulfate injection, metharbital, paramethadione, phenytoin sodium, valproate sodium, clobazam, sulthiame, dilantin, diphenylan and L-5-hydroxytryptophan.
The aroyl amino acyl pyrrole compounds of the present invention have been previously disclosed and taught as useful anticonvulsants, Richard J. Carmosin, John R. Carson, Philip M. Pitis, Anticonvulsant Aroyl Amino Acyl Pyrroles, U.S. Pat. No. 5,332,736. The compounds of the present invention, however, have not previously been shown as effective for the treatment of neuropathic pain. It is an object of the present invention to teach a method for the treatment of neuropathic pain using the compounds of the present invention.
Briefly, there is provided by the present invention a method for the treatment of neuropathic pain comprising the step of administering to a mammal suffering from such condition an effective amount, in a pharmaceutically acceptable carrier, of an active compound of the formula: 
wherein, 
A is simultaneously both
n is an integer from 1 to 5;
R1 is selected from the group consisting of H and C1-4alkyl;
R2 and R3 are selected from the group consisting of H and C1-4alkyl;
R4 and R5 are independently selected from the group consisting of H, C1-4alkyl, phenyl C1-4 alkyl and substituted phenyl C1-4 alkyl where the substituent is on phenyl and selected from the group consisting of methyl and methoxy, or in the alternative, are fused and together with said nitrogen form a heterocyclic ring selected from the group consisting of 4-[bis(4-fluorophenyl)methylene]-piperidin-1-yl, 1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolin-2-yl, 
xe2x80x83wherein Y is S or O, x is 3 to 7 and R7 is selected from the group consisting of methyl and hydroxymethyl; and
R6 is selected from the group consisting of halo, C1-4 alkyl, C1-4 alkoxy, hydroxy, nitro, amino, C1-4 acylamino, cyano, trihaloC1-4alkyl, C1-4alkylsulfonyl, C1-4alkylsulfinyl, and C1-4 acyl,
including pharmaceutically acceptable acid addition salts thereof.
The compounds of the present invention used in the treatment of neuropathic pain may be placed into two categories, those having benzoyl at the 2-position and those having benzoyl at the 4-position. Both categories of compounds may be prepared by variations of what is fundamentally the same reaction scheme.
Scheme 1 exemplifies the preparation of compounds having benzoyl at the 2-position. Referring to Scheme 1, in the first step a simple pyrrole A1 is acylated with an appropriately substituted benzoyl chloride B1 to produce benzoyl pyrrole C1. This acylation may be carried out by simply heating the benzoyl chloride and the pyrrole in an aprotic solvent followed by removing excess benzoyl chloride by reaction with a dibasic amine and extraction with HCl. Typical of the aprotic solvents which may be utilized are aromatic hydrocarbons, such as, benzene, toluene, xylene, chlorobenzene, nitrobenzene, etc.; paraffins, such as, methyl cyclohexane, octane, etc.; halocarbons, such as, methyl chloride, chloroform, tetrachloroethane, etc.; ethers, such as, diethyl ether, diglyme, etc.; ketones, such as, methyl ethyl ketone, cyclohexanone, etc.; esters, such as, ethyl butyrate, etc.; nitroalkanes, such as, nitropropane, etc.; or carbon disulfide. The temperature of the acylation will vary depending upon the desired rate of reaction and the substituents of pyrrole A1. Preferably the acylation is carried out at a temperature of from about 50 to 250xc2x0 C. A suitable dibasic amine is dimethyl-3-aminopropyl amine. In the case where R1 is hydrogen the acylation, as described, may not produce desirable yields. In this case, a Vilsmeier type acylation as employed by J. White and G. McGillivrey, J. Org. Chem., Vol. 42, pp 42-48, 1977 might be expeditiously employed. Subsequently, benzoyl pyrrole C1 is acylated at the 4-position in a Friedel-Crafts reaction with acid chloride D1 to produce 2-benzoyl-4-alkanoyl pyrrole E1. The Friedel-Crafts reaction is carried out by refluxing the carboxylic acid chloride D1, in which X is Cl, Br or l, with product C1 in a solvent with a Friedel-Crafts reagent followed by treatment with HCl and evaporation of the solvent. Suitable Friedel-Crafts reagents include aluminum chloride, zinc chloride, BF3 or TiCl4. Suitable solvents include methylene chloride, 1,2-dichloroethane, carbon tetrachloride or chloroform. The temperature of reflux might vary between about 30 and 150xc2x0 C. In the case where R6 is amine, it will not survive the Friedel-Crafts reaction in good yield. Thus, it should be protected with well known protecting groups or present as a suitable precursor substituent, such as, nitro which can thereafter be converted to amine. In the third reaction, 2-benzoyl-4-alkanoyl pyrrole E1 is aminated with amine F1 to produce the desired 2-benzoyl-4-aminoalkanoyl pyrrole G1. The amination may be carried out by heating the reactants E1 and F1 neat or in a solvent to a temperature of from about 40 to 120xc2x0 C. and preferably from about 50 to 90xc2x0 C. Suitable solvents, where employed, include ethanol, i-propanol or toluene. 
Scheme 2 exemplifies the preparation of compounds having benzoyl at the 4-position. Except for the specifics of the reactants, each step of Scheme 2 is analogous to the corresponding step of Scheme 1 with the reactions and description thereof being identical. Referring to Scheme 2, in the first step a simple pyrrole A2 is acylated with an appropriately substituted alkanoyl chloride B2 to produce alkanoyl pyrrole C2. Subsequently, alkanoyl pyrrole C2 is acylated at the 4-position in a Friedel-Crafts reaction with benzoic acid chloride D2 to produce 2-alkanoyl-4-benzoyl pyrrole E2. In the third reaction, 2-alkanoyl-4-benzoyl pyrrole E2 is aminated with amine F2 to produce the desired 2-aminoalkanoyl-4-benzoyl pyrrole G2. 
Preferred R1 include hydrogen, methyl, ethyl, n-propyl and i-propyl. In the most preferred compounds, R1 is methyl.
Preferred R2 and R3 include hydrogen, methyl, ethyl, n-propyl and i-propyl. In the most preferred compounds, R2 and R3 are hydrogen and methyl.
Preferred R4 and R5, where independently selected, include hydrogen, methyl, ethyl, n-propyl, i-propyl, benzyl and 2-phenyleth-1-yl where the phenyl ring may be mono- or di-substituted with a substituent selected from the group of methyl and methoxy. In the most preferred compounds, R4 and R5, where independently selected, are hydrogen, methyl and in at most one instance benzyl.
Preferred R4 and R5, where fused and depicted together with nitrogen, include 4-[bis(4-fluorophenyl)methylene]-piperidin-1-yl, 1 ,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolin-2-yl, 
In the most preferred compounds, R4 and R5, where fused and depicted together with nitrogen, are piperidine-1-yl, pyrrolidin-1-yl, morpholin-1-yl and imidazol-1-yl.
Preferred R6 include bromine, chlorine, methyl, ethyl, methoxy, ethoxy, hydroxy, nitro, amino, formylamino, acetylamino, cyano, perfluoromethyl, 3,3,3-trifluoropropyl, methylsulfonyl, methylsulfinyl, formyl, and acetyl. In the most preferred compounds, R6 is non-existent, methyl or chloro.
The compounds herein readily form pharmaceutically acceptable acid addition salts. Such salts include hydrochlorides, sulfates, phosphates, methane sulfonates, fumarates, maleates, citrates, lactates, and the like. Those skilled in the art will readily recognize suitable methods for manufacture and use of the acid addition salts.
The compounds of the present invention are useful in the treatment of neuropathic pain. The use of the compounds in treating neuropathic pain was determined using an animal model. This model was developed and first described by S. H. Chung and J. M. Chung, An Experimental Model for Peripheral Neuropathy Produced by Segmental Spinal Nerve Ligation in the Rat, Pain, 1992, 50, 355-363 (referred to hereinafter as the xe2x80x9cChung Modelxe2x80x9d).
Male Sprague-Dawley rats, weighing approximately 200 g each were anesthetized with isoflurane. The spinal nerve at the level of L5 was exposed through an incision just left of the dorsal midline and tightly ligated with 6-0 silk. At various times after surgery, animals were tested for mechanical allodynia with von Frey hairs (monofilaments which are calibrated to bend under a certain amount of pressure, ranging from 0.41 to 15.1 g). In order to calculate a paw withdrawal threshold (PWT), tactile allodynia was measured by recording the pressure at which the affected paw was withdrawn from graded stimuli according to the procedure of S. R. Chaplan, J. W. Pogrel, T. L. Yaksh, Role of Voltage-Dependent Calcium Channel Subtypes in Experimental Tactile Allodynia, J. Pharmacol. Exp. Ther. 1994, 269, 1117-1123. Normal rats can withstand at least 15 g of pressure without responding. Operated rats, however, can respond to as little as 0.25 g of pressure. The surgery was deemed successful if the animal responded with a PWT of less than 4 g of pressure applied to the affected paw.
The sham operation consisted of a similar surgery; the spinal nerve was visualized without being ligated. These animals were also tested for mechanical allodynia and showed no response to greater than 15 g of force applied to the ipsilateral paw. The results of the assay were expressed as percent of the maximum possible effect (% MPE), calculated as the PWT at the time of testing minus the baseline PWT divided by the maximum PWT (15 g) minus the baseline PWT times 100.
The compounds of the present invention indicated in Table 1 were tested for activity against neuropathic pain by being dissolved or suspended in either water or hydroxypropyl methylcellulose, respectively. Postoperative animals between 14 to 42 days were fasted overnight prior to dosing. Animals were orally dosed and dosage volumes were calculated on a 4 mL/kg basis. The screening dose employed was 30 mg/kg.
The compounds of the present invention listed in Table 1 include compounds of the formula: 
wherein Ar, R1, R2, R3, R4 and R5 are selected concurrently from the group consisting of:
The results of the xe2x80x9cChung Modelxe2x80x9d study are statistically significant and suggest that the compounds of the present invention are effective in reducing neuropathic pain. For treating neuropathic pain, the compounds of the present invention may be employed at a daily dosage in the range of about 30 to 2000 mg, usually in 2 to 4 divided doses, for an average adult human. A unit dose would contain about 10 to 500 mg of the active ingredient. More generally, for mammals, the treatment would comprise the daily administration of from about 0.5 mg/kg to about 50 mg/kg.
To prepare the pharmaceutical compositions of this invention, one or more compounds of the present invention are intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral, by suppository, or parenteral. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as, for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. Suppositories may be prepared, in which case cocoa butter could be used as the carrier. For parenterals, the carrier will usually comprise sterile water, though other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful, suppository and the like, from about 10 to about 500 mg of the active ingredient.